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Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging
- Source :
- Redox Biology, Vol 17, Iss , Pp 259-273 (2018)
- Publication Year :
- 2018
- Publisher :
- Elsevier, 2018.
-
Abstract
- Accumulation of senescent cells over time contributes to aging and age-related diseases. However, what drives senescence in vivo is not clear. Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals. Ercc1-/∆ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1-/∆ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1-/∆ mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1-/∆ mice never exceeded that observed in old WT mice. Surprisingly, levels of reactive oxygen species (ROS) were increased in tissues of Ercc1-/∆ mice to an extent identical to naturally-aged WT mice. Increased enzymatic production of ROS and decreased antioxidants contributed to the elevation in oxidative stress in both Ercc1-/∆ and aged WT mice. Chronic treatment of Ercc1-/∆ mice with the mitochondrial-targeted radical scavenger XJB-5–131 attenuated oxidative DNA damage, senescence and age-related pathology. Our findings indicate that nuclear genotoxic stress arises, at least in part, due to mitochondrial-derived ROS, and this spontaneous DNA damage is sufficient to drive increased levels of ROS, cellular senescence, and the consequent age-related physiological decline. Keywords: Reactive oxygen species, Free radicals, Genotoxic stress, Oxidative lesions, Endogenous DNA damage, Cellular senescence, Aging
- Subjects :
- Medicine (General)
R5-920
Biology (General)
QH301-705.5
Subjects
Details
- Language :
- English
- ISSN :
- 22132317
- Volume :
- 17
- Issue :
- 259-273
- Database :
- Directory of Open Access Journals
- Journal :
- Redox Biology
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.9a5a11c481f443f90c56186ddad5c93
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.redox.2018.04.007